Methods of Non-a-Amino Acid Synthesis, 2nd Edition

175

7

Aminocyclic

andHeterocyclic

Amino Acids

This chapter will discuss cycloalkanes that have an amino group and a carboxyl

group on the ring or attached to a ring via pendant alkyl units. The place to begin a

discussion of such molecules is perhaps with the three-, four-, ve-, and six-mem-

bered ring derivatives. Of the two possible cyclopropaneamino acids, the 1-amino

derivative is an α-amino acid, but 1 is a β-amino acid. Apart from the α-amino

acid, there are two non-α-amino acid structures for aminocyclobutanoic acids, 2

(2-aminocyclobutane-1-carboxylic acid) and 3 (3-aminocyclobutane-1-carboxylic

acid). The non-α-amino acid cyclopentanecarboxylic acid

NH

2

CO

2

H

HO

2

C

NH

2

R

R

12

1

2

3

4

1

2

3

4

CO

2

H

NH

2

CO

2

H

NH

2

R

R

1

2

3

4

5

1

2

3

4

5

34

CO

2

H

NH

2

5

derivatives have an amino group at C

2

or C

3

relative to the carbon bearing the carboxyl

group, so the two variations are 4 (2-aminocyclopentane-1-carboxylic acid) and 5

(3-aminocyclopentane-1-carboxylic acid). The non-α-amino acid derivatives involv-

ing six-membered rings lead to 1,2-, 1,3-, and 1,4-aminocyclohexanecarboxylic acid

derivatives. The 1,2-derivatives are represented by 6 (2-aminocyclohexane-1-carbox-

ylic acid), the 1,3-derivatives are represented by 7 (3-aminocyclohexane-1-carboxylic

acid), and the 1,4-derivatives are represented by 8 (4-aminocyclohexane-1-carbox-

ylic acid).

1

There are other cyclic amino acids of this type based on other rings, of

course, and several will be presented in succeeding examples.

NH

(CH

2

)

n

9

CO

2

H

NH

2

CO

2

H

NH

2

CO

2

H

NH

2

R

R

R

1

2

3

4

5

6

1

1

2

2

3

3

4

4

5

5

6

6

6

7

8

1

2

3

HOOC

1

For binding of 7 with the kringle 2 (K2) module of human plasminogen (Pgn), see Marti, D.N.;

Schaller, J.; Llinás, M. Biochemistry 1999, 38, 15741.

176

Methods of Non-α-Amino Acid Synthesis, Second Edition

A different class of cyclic amino acids is derived from heterocycles, speci-

cally reduced heterocyclic rings with a nitrogen in the ring and a pendant carboxyl

group. The generic structure 9 shows that rings of different sizes are possible (azeti-

dine, pyrrolidine, piperidine, etc.) with the carboxyl moiety at the α-, β-, or γ-position

relative to the ring nitrogen. Formally, this class of amino acids will include aziri-

dinecarboxylic acids, which are actually α-amino acids. The non-α-amino acids

will include azetidinecarboxylic acids, pyrrolidinecarboxylic acids (including the

α-amino acid proline), piperidinecarboxylic acids, and so on.

There is a class of amino acids based on acyclic compounds in which the amino

and carboxyl moieties are not directly attached to the ring but rather attached to the

ring via carbon “spacers.” One interesting example is known as gabapentin, 10. It is

a GABA analog developed for the treatment of epilepsy, but is also used to relieve

neuropathic pain, which is often due to damage to the nerve bers, or those bers

may be dysfunctional or injured.

2

Gabapentin (Gpn) can be used in the design of

well-folded hybrid peptides, and several internally hydrogen-bonded structures have

been demonstrated in the solid state for Gpn-containing peptides.

3

Another example of this last structural class of amino acids is trans-4-

(benzyloxycarbonylaminomethyl)cyclohexanecarboxylic acid (11),

4

which was con-

verted to 12. Carbamate salt 12 functioned as a transdermal permeation enhancer.

4

NH

2

CO

2

H

10

CO

2

H

NHCbz

CO

2

C

12

H

25

H

3

N

CO

2

C

12

H

25

HN

O

O

–

+

11 12

7.1 AMINOCYCLOALKYLCARBOXYLIC ACIDS

FROM CYCLIC PRECURSORS

An important strategy to prepare cyclic amino acids begins with cyclic precursors, and

subsequent refunctionalization of existing groups gives a new amino acid. If a cyclic

amino acid is commercially available, this approach is quite attractive for synthetic

modication, but a variety of functionalized cyclic precursors have been employed.

7.1.1 lactam-based syntheses

Lactams are cyclic molecules that are obvious synthetic precursors to cyclic amino

acids that have the nitrogen in the ring, usually by refunctionalization or reduction

reactions. Further, β-lactams are important precursors to β-alanine derivatives, as

well as cyclic amino acid derivatives.

Cyclic amino acids in which the nitrogen is not part of the ring can also be

prepared, typically via cycloaddition reactions with cyclic alkenes. Reaction of

2

See Sills, G.J. Curr. Opin. Pharmacol. 2006, 6, 108.

3

Vasudev, P.G.; Chatterjee, S.; Shamala, N.; Balaram, P. Acc. Chem. Res. 2009, 42, 1628.

4

Vávrová, K.; Hrabálek, A.; Doležal, P.; Holas, T.; Klimentová, J. J. Controlled Release 2005, 104, 41.